Hydrogels and organogels produced from the self-assembly of synthetic polymers have an inexhaustible potential to serve as a delivery matrix for a vast range of pharmaceutical, cosmetic and dietary products. Recent developments in polymer chemistry have enabled polymers to be synthesized with well-controlled composition and architecture. Highly versatile orthogonal functionalization strategies also allow gelation of such polymers and containment of drug payload through one or a combination of the following association mechanisms: hydrophobic interactions, ionic interactions, hydrogen bonding, physical entanglement of macromolecules and chemical crosslinking of the matrix.
A number of physical gel systems have been formulated using the ‘ABA’-type triblock copolymers, and the polymeric amphiphiles can be designed with either the ‘A’ or ‘B’ constituent blocks to be hydrophilic or hydrophobic. Many of such systems engage the use of poly(ethylene glycol) (PEG) as the uncharged hydrophilic constituent block for its biocompatibility and non-toxicity. As for hydrophobic portion(s), some of commonly selected blocks are poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(glycolide) (PGA), and poly(caprolactone) (PCL), which can be prepared either as the middle ‘B’ block (e.g., PEG-b-PGA-b-PEG) or as the terminus ‘A’ blocks (e.g., PLLA-b-PEG-b-PLLA). Aqueous mixture of enantiomeric triblock copolymers of the PLLA and PDLA-containing polymers could also give rise to physical gels formed via stereocomplexation.
Polymeric gel systems can be broadly classified as organogels or hydrogels, depending on the dispersion media used. Organogels have an organic liquid phase that is immobilized by a 3D physically crosslinked network of intertwined fibers of self-assembled polymer chains. Various kinds of organic material can be used to make up the liquid phase (e.g., organic solvents, mineral oil, plant oil, and combinations of the foregoing). Organogels are mainly used for cosmetics/dietary applications while relatively much fewer organogels are being evaluated as drug/vaccine delivery matrices. This is primarily due to the scarce amount of information available regarding the toxicology and biocompatibility of the gel-forming polymers and their degraded products. Nevertheless, when toxicity concerns are circumvented, organogels have potential for use as topical formulations owing to the enhanced dermal permeation capacities of typical organogels. Alternative modes of application include oral and trans-mucosal as well as subcutaneous depot injections. Herein, a depot is a body area in which a substance (e.g., a drug) can be accumulated, deposited, or stored and from which it can be distributed. A depot injection is an injection of a substance in a form that tends to keep it at or near the site of injection so that absorption occurs over a prolonged period.
Hydrogels, which are prepared in water, are more widely-studied compared to organogel systems. Most of the commonly used hydrogel-forming ‘ABA’-type triblock copolymers (e.g., PLLA-b-PEG-b-PLLA and PCL-b-PEG-b-PCL) require high polymer concentration and hydrophobic content for hydrogel formation. For instance, (PLLA-b-PEG-b-PLLA) containing lactide content of 17 wt. % to 37 wt. % requires a minimum concentration of about 16 wt. % of the triblock copolymer for gelation. Such a high proportion of hydrophobic constituents could give rise to adverse physiological effects during in vivo degradation. Thus, it is desirable to develop polymeric materials that can form hydrogels at a low concentration.
According to a 2008 World Health Organization (WHO) survey, breast cancer comprises of 22.9% of all cancers (excluding non-melanoma skin cancer) and its mortality rate is around 13.7% worldwide. In Europe, the incident rate of breast cancer is even higher, reaching 28%. Treatment of breast cancer may vary according to the size, stage and rate of growth, as well as the type of tumor. There are currently three main categories of adjuvant, or post-surgery, therapy. These include hormone-blocking therapy, chemotherapy and monoclonal antibodies (mAbs) therapy. The latter involves the utilization of mAbs to target specific cells or proteins towards the treatment of disease by inducing, enhancing, or suppressing an immune response. It can be used in conjunction with either hormone-blocking therapy or chemotherapy to enhance the efficacy of cancer treatment.
Studies have shown that the human epidermal growth factor receptor 2 (HER2) genes are amplified and/or overexpressed in 20% to 25% of invasive breast cancers. These HER2-positive breast cancers have significantly lower survival rates compared to HER2-negative breast tumors. The HER2-positive breast tumors are most likely to show unrestrained growth and division of cells, thus increasing the incidence of cancer development. Herceptin is a recombinant humanized mAb that can selectively bind to HER2 proteins, thereby regulating the otherwise uncontrollable cancer cell growth. It is also a US Food and Drug Administration (FDA)-approved therapeutic for the treatment of HER2-positive breast cancer. Intravenous administration is the current mode of herceptin delivery in most clinics. However, many controversies surround the optimal mode of delivery in terms of duration and dosage. Recently, F Hoffmann-La Roche reported a phase 3 clinical trial (HannaH study) involving the subcutaneous (versus intravenous) administration of (neo)adjuvant herceptin in patients with HER2-positive breast cancer. The formulation contained a fixed dose of herceptin and recombinant human hyaluronidase (rHuPH-20), a class of enzymes that temporarily degrades interstitial hyaluronan in the subcutaneous space, as an excipient. The study found that therapeutic efficacy of subcutaneous delivery of herceptin was comparable to the traditional intravenous route but the therapy had the advantage of improved patient convenience, better compliance, reduced pharmacy preparation times, and optimization of medical resources.
The foregoing illustrates that an ongoing need exists for more efficacious drug and antibiotic formulations. More specifically, formulations are needed for improved efficacy of subcutaneous treatments used in cancer therapy.